A recursive molecular docking coupled with energy-based pose-rescoring and MD simulations to identify hsGC βH-NOX allosteric modulators for cardiovascular dysfunctions

Abstract

Modulating the activity of human soluble guanylate cyclase (hsGC) through allosteric regulation of the βH-NOX domain has been considered as an immediate treatment for cardiovascular disorder (CVDs). Currently available βH-NOX domain-specific agonists including cinaciguat are unable to deal with the conundrum raised due to oxidative stress in the case of CVDs and their associated comorbidities. Therefore, the idea of investigating novel compounds for allosteric regulation of hsGC activation has been rekindled to circumvent CVDs. Current study aims to identify novel βH-NOX domain-specific compounds that can selectively turn on sGC functions by modulating the conformational dynamics of the target protein. Through a comprehensive computational drug-discovery approach, we first executed a target-based performance assessment of multiple docking (PLANTS, QVina, LeDock, Vinardo, Smina) scoring functions based on multiple performance metrices. QVina showed the highest capability of selecting true-positive ligands over false positives thus, used to screen 4.8 million ZINC15 compounds against βH-NOX domain. The docked ligands were further probed in terms of contact footprint and pose reassessment through clustering analysis and PLANTS docking, respectively. Subsequently, energy-based AMBER rescoring of top 100 low-energy complexes, per-residue energy decomposition analysis, and ADME-Tox analysis yielded the top three compounds i.e. ZINC000098973660, ZINC001354120371, and ZINC000096022607. The impact of three selected ligands on the internal structural dynamics of the βH-NOX domain was also investigated through molecular dynamics simulations. The study revealed potential electrostatic interactions for better conformational dialogue between βH-NOX domain and allosteric ligands that are critical for the activation of hsGC as compared to the reference compound.

Graphical Abstract

Highlights

• Scoring capability of QVina, Vinardo, Smina, PLANTS, and LeDock were assessed against the hsGC βH-NOX specific active and decoy dataset.

• Target biasness was achieved whilst screening by retaining two out of three substructures in screened compound that are critical for heme-independent hsGC βH-NOX activation.

• Target-specific biasness was further ensured by preserving the interactions of functionally important residues in the top three hits.

• MM-GB/PBSA yields energetically favored docked complexes.

• Principal Component Analysis (PCA) exhibited noticeable fluctuations in ligand-binding regions of the active-site that are responsible for heme and NO- independent activation.

Keywords:

• Molecular docking
• scoring function evaluation
• human soluble guanylate cyclase
• molecular dynamics simulations
• clustering
• per-residue energy decomposition

Acknowledgements

Support by the High Performance Computing facility of “Sezerman Lab” Acibadem M. A. A. University is acknowledged.

Author contributions

A.R.S., O.U.S., and R.R.K., conceived and designed the experiments; R.R.K. performed the experiments; R.R.K., A.M. and S.S.C. analyzed the data; R.R.K wrote the paper; A.R.S., A.M., and O.U.S revised and improved the paper.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The authors would also like to thank the International Research Support Initiative Program (IRSIP), National Research Program for Universities (NRPU-4050) by Higher Education Commission (HEC) Pakistan and 2216 Research Fellowship Program for International Researchers by TUBITAK.